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Dysfunction of these transporters has been implicated in the pathogenesis of various neurological disorders. Previous studies have shown that venom from the spider <jats:italic>Parawixia bistriata<\/jats:italic> and a purified compound (Parawixin1) stimulate <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>2 activity and protect retinal tissue from ischemic damage. In the present study, the <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>2 subtype specificity of this compound was explored, employing chimeric proteins between <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>2 and <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>3 transporter subtypes and mutants to characterize the structural region targeted by the compound. This identified a critical residue (Histidine\u201071 in <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>2 and Serine\u201045 in <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>3) in transmembrane domain 2 (<jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content>2) to be important for the selectivity between <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>2 and <jats:styled-content style=\"fixed-case\">EAAT<\/jats:styled-content>3 and for the activity of the venom. Using the identified residue in <jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content>2 as a structural anchor, several neighboring amino acids within <jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content>5 and <jats:styled-content style=\"fixed-case\">TM<\/jats:styled-content>8 were identified to also be important for the activity of the venom. This structural domain of the transporter lies at the interface of the rigid trimerization domain and the central substrate\u2010binding transport domain. Our studies suggest that the mechanism of glutamate transport enhancement involves an interaction with the transporter that facilitates the movement of the transport domain.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13047-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>We identified a domain (purple star) in the glutamate transporter EAAT2 that is important for transport stimulation through a spider venom, and suggest a mechanism for enhanced transporter function through facilitated substrate translocation (arrow). Because the dysfunction of glutamate transporters is implicated in the pathogenesis of neurological disorders, understanding the mechanisms of enhanced transport could have therapeutic implications.<\/jats:p>","DOI":"10.1111\/jnc.13047","type":"journal-article","created":{"date-parts":[[2015,1,27]],"date-time":"2015-01-27T15:21:09Z","timestamp":1422372069000},"page":"199-210","source":"Crossref","is-referenced-by-count":20,"title":["Molecular determinants of transport stimulation of <scp>EAAT<\/scp>2 are located at interface between the trimerization and substrate transport domains"],"prefix":"10.1111","volume":"133","author":[{"given":"Ole V.","family":"Mortensen","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology Drexel University College of Medicine Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 L.","family":"Liberato","sequence":"additional","affiliation":[{"name":"Neurobiology and Venoms Laboratory Department of Biology College of Philosophy Sciences and Literature of Ribeir\u00e3o Preto University of S\u00e3o Paulo Ribeir\u00e3o Preto SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaquim","family":"Coutinho\u2010Netto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology Ribeir\u00e3o Preto School of Medicine University of S\u00e3o Paulo SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wagner F.","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Neurobiology and Venoms Laboratory Department of Biology College of Philosophy Sciences and Literature of Ribeir\u00e3o Preto University of S\u00e3o Paulo Ribeir\u00e3o Preto SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9ia C. 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